The major objective of our research proposal is to determine the mechanisms by which local anesthetics and guanidine derivatives inhibit glycogenolysis and gluconeogenesis in the liver. Especially, we want to evaluate the importance of ion redistribution and trans-membrane potential changes in respect to the hypoglycemic effects of these agents. The role of individual ions affected by these agents in respect to their hypoglycemic action will be evaluated and the enzymatic step(s) blocked in these pathways localized. The importance of membrane depolarization in respect to the hypoglycemic effect will be determined. The possibility that the effect of local anesthetics involves protein conformation changes in membranes will be measured by the tritium exchange technique; ion fluxes, membrane potential measurements, and metabolites assay will be performed in a haemoglobin-free in situ perfused rat liver.